Skin cancer, already the most common maligna11ncy in the US, has an increasing incidence secondary to increasing risk factors (aging population and increasing UV irradiation). The increasing societal burden (= approximately $500 million/year) coupled with the potential translation of knowledge toward other malignancies strongly supports the study of skin cancer prevention. Researchers have observed a strong association between skin carcinogenesis and increased concentrations or activity in the skin of polyamines or ornithine decarboxylase (ODC), the rate-limiting polyamine biosynthetic enzyme. Conversely, inhibitors of ODC have been observed to prevent cancers in many preclinical cancer models including skin. Alpha-difluoromethylomithine (DFMO) an orally administered, specific inhibitor of ODC has been observed in early human studies to produce significant depletion of polyamines or ODC in the skin and other tissues. Phase I and II clinical chemoprevention studies of DFMO at the University of Wisconsin led to the pursuit of an NCI-sponsored, single institution phase III skin cancer prevention study of DFMO vs. placebo in subjects with a prior history of skin cancer. Even though this study is on goal (334 subjects accrued in < 2 years) to complete the objectives, a delayed start and greater than expected subject dropout after randomization require continuing the study beyond the original requested/funded time frame. Primary objective: Will subjects with a prior history of skin cancers taking DFMO have a decrease in new skin cancers as compared to placebo controls? (291 subjects randomized, currently 192 subjects on study with = 850 patient-years of follow-up out of a planned 1100 patient years). Secondary objectives: Will inhibition of induced-ODC activity or polyamine levels in skin be validated as an intermediary marker for DFMO as a chemoprevention agent? (291 subjects underwent biomarker biopsies at baseline, = 130 subjects at 24 months, less than or equal too 60 subjects at 36 and 48 months) Will the frequency or severity of DFMO adverse events be acceptable to subjects over a 3-5 year period. (Ototoxicity and gastrointestinal toxicity have been most common). The objectives, which are unchanged from our original proposal, are all on schedule to be completed in the next 1-2 years.